Project Summary It is well known that stressful events, such as those occurring as a result of COVID-19 prevention efforts, are a potent trigger for the initiation and escalation of illicit substance use. However, it is not well known how stress triggers increased substance use, which could help improve understanding, prevention, and treatment of substance use disorders. Therefore, our ongoing longitudinal study of adolescents was designed to test the hypothesis that stress during development recalibrates the neural processes underlying threat and reward reactivity as well as working memory capacity, which leads to increased risk for the initiation and escalation of substance use. Because COVID-19 related social distancing is a profound stressor, measuring it?s effects provides an opportunity to better understand these hypothesized pathways by which stress increases substance use. Therefore, we propose to recontact adolescents (n=309) and caregivers (n=246) in our ongoing longitudinal study to assess changes in stress, cognitive function, and substance use due to the COVID-19 pandemic at two time points. At both time points, youths will also complete a working memory capacity task and delay discounting assessment and have their locations tracked with GPS for a week while they receive 35 ecological momentary assessment (EMA) prompts to assess their momentary stress, social interactions, substance use, and feelings at particular locations as was done in prior waves. In Aim 1, we focus on 3 particular categories of stress to understand their relative contribution to increased substance use: (1) Social distancing experiences: the GPS and questionnaire assessments of activity patterns provide a quantitative, state-of-the-art measure of the magnitude of change in individual mobility elicited by COVID-19 social distancing; (2) Economic hardship: Because our sample is socioeconomically diverse (37.4% have annual household incomes under $30,000), we will have the opportunity to clarify the effects of increased economic challenges on substance use; (3) Social isolation and conflict: The questionnaire and EMA data on frequency of interpersonal interaction and conflict provide the opportunity to determine if these are also triggers of increased substance use. In Aim 2, potential cognitive mediators of these effects will be assessed using the measurement of working memory capacity and delay discounting. These youths have already completed a neuroimaging session that assessed neural structure (anatomy and connectivity), resting state activity, and activity during tasks probing working memory capacity (Emotional N-Back), reward reactivity (viewing images of marijuana, e-cigs, and alcohol), reward anticipation (Monetary Incentive Delay), and threat reactivity (emotional faces). Because these same procedures will be repeated as soon as research activity can resume after COVID-19 restrictions are lifted, Aim 3 will be to determine how COVID-19 related stress moderates changes in neural structure and function as well as the degree to which these neural changes predict changes in substance use.